Improvement of dyslipidemia, insulin sensitivity, and energy balance by a peroxisome proliferator-activated receptor alpha agonist.
Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor family of ligand-activated transcription factors. It plays an important role in the regulation of genes involved in lipid metabolism and transport. Compound A is a potent and orally active PPARalpha agonist that activated both human and rat PPARalpha receptors. The compound induced the expression of genes involved in fatty acid metabolism in a rodent hepatoma cell line and in the liver of db/db mouse. The ability of compound A to stimulate fatty acid beta-oxidation was demonstrated in human hepatocytes and human skeletal muscle cells, which confirmed a functional activation of PPARalpha-mediated activities. Compound A was shown to be a more potent and efficacious antidyslipidemic agent in atherogenic rat and db/db mouse models as compared with fenofibrate. The increase in high-density lipoprotein cholesterol levels by compound A was at least partially due to an increase in serum apolipoprotein A-I protein concentrations in human PPARalpha transgenic mouse. The triglyceride-lowering effect was further confirmed in a higher species, obese dog models. In addition, compound A dose-dependently ameliorated hyperglycemia and hyperinsulinemia, and improved glucose tolerance in db/db mice. In a diet-induced obesity mouse model, compound A decreased body weight mainly by increasing energy expenditure and reducing fat deposition. In conclusion, the novel and potent PPARalpha agonist improves lipid profile, insulin sensitivity, and energy balance in animal models.
Chen
Xiaoli
X
Endocrine Therapeutics and Metabolic Disorders, Johnson & Johnson Pharmaceutical Research and Development, LLC, Spring House, PA, USA. shirley_chen@merck.com
Matthews
Jay
J
Zhou
Lubing
L
Pelton
Patricia
P
Liang
Yin
Y
Xu
Jun
J
Yang
Maria
M
Cryan
Ellen
E
Rybczynski
Philip
P
Demarest
Keith
K
D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D050171:Dyslipidemias / Q000188:drug therapy*; D004734:Energy Metabolism / Q000187:drug effects*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006946:Hyperinsulinism / Q000188:drug therapy; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000819:agonists*; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
D016632:Apolipoprotein A-I; D005227:Fatty Acids; D007189:Indans; D008055:Lipids; D047493:PPAR alpha; D010671:Phenylurea Compounds